Asthma and allergy are closely related and develop because of both a genetic predisposition as well as environmental exposures. Elevated total serum IgE levels are closely associated with atopy and bronchial hyperresponsiveness (BHR), both of which are characteristic of allergic asthma. These disorders are not inherited as simple Mendelian traits. Family studies of atopic allergy and asthma have been unable to clearly delineate the number of, or mode of, inheritance of major genes involved in these disorders. Thus, studies on the genetic regulation of IgE levels are relevant to understanding the pathophysiology of allergy, BHR and asthma. The purpose of this application is to investigate genetics related to IgE levels and BHR, important components of asthma. The applicants have recently performed segregation analysis on 92 Dutch families ascertained through an asthmatic parent, which provided evidence for two independent loci, accounting for 50% and 19% respectively, of the variance in IgE levels observed in the families. Furthermore, they have localized one of the major gene(s) that regulate total serum IgE to chromosome 5q. Linkage analyses suggest this gene(s) is located near important candidate immunoregulatory genes that regulate total serum IgE levels. In addition, the applicants have found evidence for linkage of BHR to the response to histamine challenge, which maps to this same area of 5q. These findings represent a major step in mapping genes important in the regulation of allergic and asthmatic responses, and in delineating their role in the pathogenesis of allergic asthma. The major objectives of this application are to further define and extend the initial segregation analysis and genetic linkage findings. The sequence of candidate genes on chromosome 5q will be examined for mutations in allergic asthmatics as compared to controls. In addition, because a second, as of yet unidentified, allergy locus is evident from the segregation analysis, various immunoregulatory genes throughout the genome which are potentially important in the regulation of the allergic and asthmatic responses will be examined for linkage to IgE and BHR. Because the linkage data on chromosome 5q suggests the location of a susceptibility gene in or around the cytokine gene cluster, the role of various cytokines in the pathogenesis of allergy and asthma will be explored. Cytokines are obvious candidates since they are important in regulating inflammatory cell responses and IgE synthesis. Polymorphisms in the cytokines (IL-3, IL-4, IL-5, IL-9, IL-12, IL-13 and GM-CSF) located on 5q31-33 will be evaluated for linkage to IgE levels and BHR. Other cytokine loci will initially be studied for linkage with IgE and BHR using flanking polymorphic markers. If linkage is found, these cytokines will be examined for polymorphisms related to IgE and BHR. It is anticipated that these studies will identify genetic mutations important in allergy and asthma.
